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Checkpoint kinases are protein kinases that are involved in cell cycle control. Two checkpoint kinase subtypes have been identified, Chk1 and Chk2. Chk1 is an Serine/threonine-specific protein kinase that in humans, is encoded by the CHEK1 gene. Chk1 coordinates the DNA damage response (DDR) and cell cycle checkpoint response. Activation of Chk1 results in the initiation of cell cycle checkpoints, cell cycle arrest, DNA repair and cell death to prevent damaged cells from progressing through the cell cycle. CHEK2 is tumor suppressor gene that encodes the protein CHK2, a serine threonine kinase. Chk2 operates in an intricate network of proteins to elicit DNA repair, cell cycle arrest or apoptosis in response to DNA damage. Mutations to the CHEK2 gene have been linked to a wide range of cancers including breast cancer.

Background

Checkpoint Kinase (Chk) is a kind of protein kinases involving cell cycle control that blocks the cell cycle after DNA damage and repairs damaged DNA, thereby maintaining the fidelity of the genome. The known checkpoint kinases include Chk1 and Chk2. Although both have overlapping substrate profiles and similar structures, they are expressed differently in different tumor cells and tissues. Both of them are mainly used as a target site for tumor cells and use selective inhibitors or combined radiotherapy and DNA damaging agents to treat tumors and related diseases. Besides, the combined use of Chk1/2 will enhance the sensitivity of antitumor by radiotherapy and chemotherapy methods.

Chk1 is a 54.4 kDa serine/threonine-specific protein kinase that plays, with Chk2, a pivotal role in maintaining DNA integrity. Chk1 includes an N-terminal kinase domain, a C-terminal domain and a phosphorylation activation site that acts on ATM kinase and ATR kinase. Chk1 is an established transducer of ATR- and ATM-dependent signaling in response to DNA damage. Chk1 is the bridge linking DNA damage and cell cycle arrest in G2 /M phase. When DNA damages, the cell cycle checkpoints of normal cell are arrested, the cell cycle transition is delayed, and damaged cells are repaired before entering mitosis with the help of inhibitor p53 and Chk1 at cell cycle checkpoints G1, S, and S, G2 phases respectively. Chk1 inhibitors are divided into ATP competitive inhibitors and non-ATP competitive inhibitors, which have an important role in the treatment of cancer. At present, the reported Chk1 inhibitors in the clinical research phase include UCN-01 (phase I/II), PF-0477736 (phase I), AZD-7762 (phase I), and J-107088 (Phase I). Other Chk1 inhibitors are in preclinical research. Chk1 plays an important role in the occurrence and development of tumors and the regulation of cell replication. In addition, combinations of Chk1 inhibitors and DNA damaging agents can enhance antitumor efficacy.

Chk2 is a 60.9 kDa serine/threonine kinase whose active site is structurally similar to those of Chk1. Chk2 is an important signal transduction protein involved in DNA repair response after DNA double-strand breaks. Activated Chk2 can phosphorylate and stabilize multiple proteins, leading to cell cycle arrest or apoptosis. Based on its role in DNA damage and cell mitosis, studies on the susceptibility of Chk2 inhibitors to increase the sensitivity of tumor cells to DNA damaging agents have been receiving extensive attention. Chk2 inhibitors can sensitize the damage of cancer cells caused by radiotherapy and chemotherapy and protect normal cells from side effects of radiotherapy. Currently, the major Chk2 inhibitors include: PV1019, CCT241533, AZD7762, XL9844, VRX0466617, C3742, ABI, Debromohymenialdisine (DBH), DBH-derived Indoloazepine, NCS109555. Some of these Chk2 inhibitors have entered phase I clinical studies, such as NSC109555, which can enhance the cytotoxic effect of cisplatin on pancreatic cancer MIA PACA-2 cells. C3742 with small-molecule can enhance the killing effect of cisplatin on P53-defective tumor cells, and the combination of XL9844 with gemcitabine suppresses tumor cells. The development of highly specific Chk2 inhibitors will promote the progress of anti-tumor therapy.